S-Nitrosylation of GPCR Regulatory Machinery as a Mechanism to Bias Signaling

Upon stimulation by endogenous ligands, G protein-coupled receptors (GPCRs) activate downstream signaling pathways through multiple mechanisms, including G protein subtypes, β-arrestins, and receptor-specific partners. Synthetic ligands may activate only a subset of these pathways, resulting in functional selectivity or signaling bias. Since not all signaling outputs are therapeutically desirable, there is pharmaceutical interest in exploiting biased signaling. Although much effort is focused on designing ligands to induce receptor conformations that result in signal bias, it is also true that cellular systems adapt dynamically in ways that tune receptor signaling, termed system bias. In this chapter, we provide evidence that posttranslational modification of receptor machinery by S-nitrosylation is an important regulator of system bias in GPCR signaling. S-nitrosylation has been reported to affect the function of multiple classes of GPCR signaling pathway components, including receptors, G proteins, G protein-coupled receptor kinases, β-arrestins, and others. Further, untargeted proteomic studies of S-nitrosylated proteins have identified over 60 GPCRs, most heterotrimeric G proteins, and numerous GPCR signaling components, hinting at a class effect and unifying mechanism to bias the functional repertoires of GPCRs in vivo. Thus, protein S-nitrosylation provides prototypic examples for how post-translational regulatory mechanisms bias GPCRs endogenously.